Members of the taxoid family of compounds, e.g. docetaxel and paclitaxel, have potent anti-tumor activities (Wang et al., Cancer 88:2619, 2000, (5,6,7)). Docetaxel inhibits microtubule dynamics by binding to beta- tubulin and blocking disassembly of alpha- and beta-tubulin heterodimers thus abrogating tumor growth. Paclitaxel (Taxol™) is a complex diterepene derived from the Pacific yew tree Taxus brevifolia (1) that also has significant anti-tumor activity. Paclitaxel primarily suppresses microtubule dynamics and interferes with spindle formation arresting cell cycle at mitosis leading to apoptosis (6,7).
The clinical use of taxoid compounds has expanded to include cancers of the breast, ovaries and lung (2-4) and is expected to expand further. As with many cancer therapeutic agents, resistance to taxoid family members remains a significant hindrance in their application as a successful chemotherapeutic drugs. Resistance to the taxoid compounds can be either inherent or acquired subsequent to treatment most likely due to emergence of a minority population. For example, Paclitaxel resistance is believed to be a multifnctorial phenomenon. The principle mechanisms underlying resistance include the overexpression of transporter protein P-glycoprotein, altered binding of paclitaxel to its cellular target, β-tubulin, mutations in the β-tubulin gene, overexpression of β-tubulin isotypes, and decreased sensitivity to apoptotic stimuli. The role of P-glycoprotein as a potential mediator of resistance has been abundantly studied. Several P-glycoprotein inhibitors have been characterized although relatively few of these, such as vempamil and cyclosporine, have shown any clinical efficacy and are frequently accompanied by dose-limiting side effects. Recently, there has been renewed effort to find novel effectors of drug resistance which could provide alternative strategies for resistance reversal.